The present invention relates to the field of cardiovascular disease and more particularly, the treatment and prevention of poor cardiac function following surgery, including, but not limited to, open heart surgery.
Poor cardiac function remains a significant problem in the post-operative period, such as the period following open heart surgery. Drugs used to treat this type of cardiac dysfunction have either forced the heart to work harder (e.g. inotropes), or decreased the work load faced by the heart (e.g. vasodilators, alpha, beta and calcium channel blockers). Unfortunately, both classes of drugs have deleterious side-effects.
For example, one of the most common inotropes used to improve cardiac function is digitalis. However, the dosage of digitalis is critical: intoxication can be fatal. While the overall level of toxicity is not clear, it has been estimated that approximately 25% of hospitalized patients taking digitalis show some signs of toxicity. See Beller et al., xe2x80x9cDigitalis intoxication: A prospective clinical study with serum level correlations.xe2x80x9d N. Engl. J. Med. 284:989 (1971).
Calcium channel blockers also have side-effects. Some, for example, are reported to aggravate myocardial ischemia. This may be due to excessive hypotension or decreased coronary perfusion. See Goodman and Gilman""s The Pharmacological Basis of Therapeutics (Pergamon Press. Eighth Edition 1990) (pgs. 774-779). While the drug verapamil is less likely to have this problem, the use of the drug is limited. Indeed, it is specifically contraindicated where there are SA or AV nodal conduction disturbances.
What is needed is a safe and effective pharmacological approach to the treatment and prevention of cardiac failure. Such a treatment should permit broad use without significant side-effects.
The present invention relates to the field of cardiovascular disease and more particularly, the treatment and prevention of poor cardiac function following an ischemic incident, a heart attack, or surgery. With regard to surgery, the procedure can be used before, during and following surgery, and the surgery can be general surgery (e.g., transplantation, such as liver transplantation) or cardiac surgery, such cardiac surgery including, but not limited to, open heart surgery. The present invention relates to new methods of treating poor cardiac performance, such as that resulting from ischemia in a surgical setting. In some embodiments, a patient with a myocardial infarction (e.g., due to occlusion of a coronary artery) is treated by the methods of the present invention.
Both treatment and prevention are contemplated. In one embodiment, the present invention contemplates a method comprising the steps of a) providing: i) a subject having symptoms of poor cardiac performance and ii) means for delivering a solution of dichloroacetate; and b) delivering said solution to said subject with said delivering means under conditions such that said subject has a blood (e.g. serum or plasma) concentration of dichloroacetate in the therapeutic range (such as a concentration of approximately 0.5 mM or greater). In another embodiment, the present invention contemplates a method comprising the steps of a) providing: i) a subject at risk of poor cardiac performance and ii) means for delivering a solution of dichloroacetate; and b) delivering said solution to said subject with said delivering means under conditions such that said subject has a blood (e.g. serum or plasma) concentration of dichloroacetate of greater than approximately 200 xcexcM, more preferably greater than 500 xcexcM, and still more preferably greater than 1 mM, for a period of time longer than 1 hour, and more preferably longer than 6 hours, and most preferably 24 hours or longer. In one embodiment, said delivering of step (b) is performed where the conditions comprise a first administration, comprising a bolus, and a second administration, wherein said second administration comprises continuous administration.
It is not intended that the invention be limited to subjects with any one type of symptom of poor cardiac function. Also, the age, sex, or degree of disease state is not intended to be in any way limiting to the present invention, although the invention can be used with particular success on children and infants, including but not limited to neonates.
The invention is also not limited by the cause of poor cardiac function, although the invention can be used with particular success with patients whose cardiac function is poor following surgery, such as open heart surgery. Of course, it is not intended that the present invention be limited to particular surgical procedures. Open heart surgery using cardiopulmonary bypass pump and aortic cross clamp is contemplated as one example of surgery putting patients at risk for poor cardiac function. This includes simple lesions such as a trial septal defect or ventricular septal defect and complex lesions such as transposition arterial switch, Tetralogy of Fallot, atrioventricular septal defect, repair of total veins, Fontan operation, etc. In some embodiments, the methods and composition of the present invention find use in the treatment of myocardial infarction (e.g., during or following thrombolysis). For example, dichloroacetate solution can be supplied during. reperfusion.
While it is not intended that the present invention be limited, by the particular delivery means. One means is an intravenous means, such as that achieved by introduction through an intravenous drip. Other means include (but are not limited to) delivery with a catheter. A preferred means involves direct injection into the aorta.
The particular dosage is also not intended to be limiting. A variety of temporal protocols is contemplated. Delivery in a bolus as well as continuous delivery is contemplated. In a preferred embodiment, dichloroacetate (such as sodium dichloroacetate) is given in a bolus of at least 100 mg/kg of an approximately 100 mg/ml solution (1.0 cc/kg bolus) and, immediately thereafter, dichloroacetate is given as an infusion at approximately 12.5 mg/kg/hr for greater than 10 hours, and more preferably, 24 hours or more.
Higher dosages are permitted. Dichloroacetate does not have significant sideeffects, although some patients experience mild drowsiness.
The following definitions are to be used to further explain the invention and should in no way be used to limit the scope of the invention.
xe2x80x9cSubjectxe2x80x9d as used herein refers to a vertebrate. Preferably, the vertebrate is a human.
xe2x80x9cCatheterxe2x80x9d as used herein refers to a device for insertion into canals, vessels, passageway or body cavities.
xe2x80x9cCardiac diseasexe2x80x9d as used herein refers to a state in which the heart of a subject is no longer able to function within normal parameters.
xe2x80x9cInternallyxe2x80x9d as used herein refers to the state of being inside the body.
xe2x80x9cTemporal protocolxe2x80x9d or xe2x80x9cdosage regimentxe2x80x9d as used herein refers to the time sequence for administration of drug, to i.e. the amount of drug given over time.